Novel relaxant effects of RPL554 on guinea pig tracheal smooth muscle contractility

Abstract

We investigated the effectiveness of RPL554, a dual PDE3 and 4 enzyme inhibitor, on airway smooth muscle relaxation and compared it with that induced by salbutamol, ipratropium bromide, glycopyrrolate or their combination on bronchomotor tone induced by different spasmogenic agents. EXPERIMENTAL APPROACHGuinea pig tracheal preparations were suspended under 1 g tension in Krebs-Henseleit solution maintained at 37°C and aerated with 95% O 2 /5% CO 2 and incubated in the presence of indomethacin (5 μM). Relaxation induced by cumulative concentrations of muscarinic receptor antagonists (ipratropium bromide or glycopyrrolate), β 2 -adrenoceptor agonists (salbutamol or formoterol), PDE3 inhibitors (cilostamide, cilostazol or siguazodan) or a PDE4 inhibitor (roflumilast) was evaluated in comparison with RPL554. Maximal relaxation was calculated (% Emax papaverine) and expressed as mean ± SEM. KEY RESULTSBronchomotor tone induced by the various spasmogens was reduced by the different bronchodilators to varying degrees. RPL554 (10-300 μM) caused near maximum relaxation irrespective of the spasmogen examined, whereas the efficacy of the other relaxant agents varied according to the contractile stimulus used. During the evaluation of potential synergistic interactions between bronchodilators, RPL554 proved superior to salbutamol when either was combined with muscarinic receptor antagonists. CONCLUSIONS AND IMPLICATIONSRPL554 produced near maximal relaxation of highly contracted respiratory smooth muscle and provided additional relaxation compared with that produced by other clinically used bronchodilator drugs. This suggests that RPL554 has the potential to produce additional beneficial bronchodilation over and above that of maximal clinical doses of standard bronchodilators in highly constricted airways of patients. AbbreviationsCFTR, cystic fibrosis transmembrane receptor; COPD, chronic obstructive pulmonary disease; RPL554, [9,10-dimethoxy-2 (2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a] IntroductionBronchodilators including β 2 -adrenoceptor agonists and muscarinic receptor antagonists are used in acute and maintenance therapy of respiratory conditions including asthma and chronic obstructive pulmonary disease (COPD) (Barnes, 2011;Cazzola et al., 2012). The clinical effectiveness of these bronchodilators may be reduced with increased disease severity and also during exacerbation of disease symptoms. Hence, there is a need to increase the magnitude of bronchodilation to obtain greater clinical benefit. One approach is the administration of long-acting β 2 -adrenoceptor agonists and muscarinic receptor antagonists in combination (Tashkin and Ferguson, 2013;Spina, 2014). Similarly, the combination of ipratropium bromide with the short-acting β 2 -adrenoceptor agonist, salbutamol, is often used in the management of acute asthma, although the added benefit of the combination over salbutamol alone has been questioned (FitzGerald et al., 1997;Garrett et al., 1997).We have pre...

Inhaled Dual Phosphodiesterase 3/4 Inhibitors for the Treatment of Patients with COPD: A Short Review

“…Venkatasamy et al have studied tracheal guinea pig smooth muscle relaxation under PDE3, PDE4 or dual PDE3/4 inhibition, alone or with muscarinic receptors antagonists and beta-2 receptor agonists and demonstrated that dual PDE3/4 inhibition alone produced significant smooth muscle relaxation with a cumulative effect when added to another bronchodilator. 40 The same synergy with other bronchodilators was found in human bronchial explants 41 regardless of airway size and therefore including small airways, 42 suggesting a potential to modulate air-trapping.…”

The short-term bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in COPD

“…Pre-clinical studies using human isolated bronchial smooth muscle preparations have demonstrated that RPL554 added to other bronchodilators caused additional bronchodilation, with some evidence of synergistic effects when combined with a muscarinic antagonist [ 9 , 10 , 15 ]. In our clinical trials, additional bronchodilation was observed when using RPL554 in combination with other bronchodilators.…”

Novel Immunomodulatory Therapies for Respiratory Pathologies

“…Despite the improvements on drug safety, some patients still suffer from gastrointestinal adverse events when treated with second generation PDE4 inhibitors ( Janjua et al, 2020 ). The scientific community is optimistic about the recent development of dual PDE3 and PDE4 inhibitors that present potent bronchodilation and anti-inflammatory effects ( Beute et al, 2018 ; Venkatasamy and Spina, 2016 ). On the other hand, the development of inhaled PDE4 inhibitors might limit their distribution to the brain and reduce side effects ( Ti et al, 2019 ).…”